One Health Research Leads to Test and Treatment for Preeclampsia

Posted November 21, 2012

College Station, TX-Many of the health problems in the world
today not only impact humans, but also animals and the environment.
To find solutions, researchers have increasingly taken a "One
Health" approach leading to the development of collaborations as
unique as the answers they seek.

One example of this One Health approach involves the work of
physicians, veterinarians, and environmental scientists at Texas
A&M University (TAMU) and Texas A&M AgriLife
Research. Dr. Jules B. Puschett, a physician and research
professor in the Veterinary Pathobiology Department at the College
of Veterinary Medicine & Biomedical Sciences (CVM), along with
researchers at Texas A&M AgriLife Research, have developed an
animal model they hope will lead to a way to predict and prevent
preeclampsia in humans.

Preeclampsia, a pregnancy-specific disorder, seen in 3-10
percent of pregnancies, is the second leading cause of maternal and
fetal death in the United States. It is also a leading
contributor to the most common cause of maternal and fetal death in
developing countries. Presently, there is nothing physicians can do
to predict, prevent, or cure this disorder.

Since there is no cure, the most common treatment for this
disorder is bed rest until the physician decides whether or not to
do a cesarean section. If the mother and child survive
delivery, the mother is at risk for having high blood pressure and
diabetes later in life, and the baby has a risk of developing
mental abnormalities.

Using a rat model, Puschett's team discovered an elevation in a
substance in preeclamptic rats that can be detected in the first
few days of pregnancy in urine and blood. In conjunction with
the discovery of this substance, these researchers have also
developed a compound that prevents preeclampsia when given to
pregnant rats with this elevated substance. Currently, the
team is in the process of collecting more data to receive U.S. Food
and Drug Administration (FDA) approval for human clinical
trials.

The team found that an elevation of the substance
marinobufagenin (MBG) not only indicates, but is a potential cause
of the later development of preeclampsia. A diagnostic test
to measure MBG was developed in collaboration with Drs. Luc
Berghman and Daad Abi-Ghanem from the TAMU Department of Poultry
Science. After this discovery, Puschett and his team, who have been
working on this project for six years, measured the blood and urine
of human patients and found that MBG was elevated in those patients
with a diagnosis of preeclampsia.

"Our intention was not only to measure MBG in the blood, but
also in the urine because if we end up trying to screen thousands
of patients, it is much easier for the patient to give you a urine
specimen than blood," Puschett said.

Their next step was to determine when the level of MBG becomes
elevated. In the preeclamptic rats, elevated levels of MBG
were present in the first few days of pregnancy.

"At that time in the pregnancy, the rats didn't yet have high
blood pressure or an excess of protein in the urine," Puschett
said. "So this is a forecast of the later development of
preeclampsia in the rat."

With this discovery, Puschett explained that, potentially, every
pregnant woman could be screened for preeclampsia through an
examination of MBG levels in urine. Once the team realized
they could predict this illness, they decided they needed to try
and prevent it, too.

Puschett approached chemists from the Laboratory for Innovative,
Chemistry, and Natural Products-Based Interdisciplinary Drug
Discovery (LINCHPIN) at TAMU, Dr. Daniel Romo, a chemistry
professor and director of the laboratory; Dr. Jing Li, co-director
of the laboratory and Dr. Xinzhong Lai, who previously worked with
Romo; and asked them to create a compound that would block MBG's
effects, thus preventing preeclampsia.

"The goal of the ongoing collaboration is to broaden the studies
of preeclampsia in the Puschett group to investigate all possible
predictive agents, which appear in the blood and urine of
preeclamptic patients, in order to identify a reliable predictor
which can be used to diagnose this disease at its earliest
developing stage," Romo said.

The group discovered resibufogenin, or RBG, may be a compound
that could be used to prevent the onset of preeclampsia.
Although it differs little from MBG, RBG binds to the MBG
substance, preventing MBG's effects.

"Collaborating with Dr. Puschett, we have discovered a potential
predictive agent (MBG), as well as an antagonist (RBG) to this
agent, which can be used to prevent preeclampsia," Romo said.

To test RBG, the compound was given to rats in early pregnancy.
Puschett said the compound completely prevented preeclampsia,
high blood pressure, and abnormal protein levels in the rats'
urine.

Currently, the team is in process of gathering enough data and
funding to present to the FDA for approval to start providing RBG
to human patients. Puschett said it would probably take two
to three years before enough data is collected to present to the
FDA. After the FDA approves the drug, the human clinical
trials for RGB will begin for pregnant volunteers who have elevated
MBG levels to see if preeclampsia is prevented.

If RBG does not prevent preeclampsia in human patients, Puschett
said there are approximately 200 compounds similar to RBG that
could be evaluated as antagonists for MBG. These compounds,
he said, could be used to help in an effort to establish a method
for "personalized medicine" in preeclampsia. Personalized
medicine is medication and treatment tailored toward the individual
needs of the patient.

"We are now planning to broaden these studies to investigate
other compounds in this family to identify additional antagonists
to these agents, which can potentially prevent and/or treat
preeclampsia," Romo said.

Puschett and his team also said they think elevated MBG levels
could be a problem in other illnesses such as brain disorders.

For right now, though, the main focus for Puschett and his team
is generating enough data to present to the FDA for approval of
human trials of RBG.

"First, we are focusing on preeclampsia patients, then we are
going to branch out to test the waters in other illnesses,"
Puschett said.